The current invention proposes topical administration of therapeutically effective doses of certain sesquiterpene epoxides (trichothecenes) to chemexfoliate selected areas of the epidermis.
Chemexfoliation has been around since the days of ancient Egypt with lactic acid from sour milk used as part of a skin rejuvenation regimen. The middle ages saw tartaric acid from old wine used for the same purpose. Modern day chemical peeling includes such pioneers as P. G. Unna who first described properties of salicylic acid, resorcinol, phenol, and trichloroacetic acid. Baker and Gordon developed deep peeling agents in the 1960s. Alpha and Beta hydroxy acids appeared over the last several decades as mild exfoliants available in many commercially available skin care products. The primary application of chemexfoliation has been, and remains today, rejuvenation of the skin by destruction or damage to the epidermis and sometimes also the dermis.
Prior art chemexfoliants in use today can be grouped into three categories; Superficial Peeling Agents, Medium Depth Peels, and Deep Peels.
Superficial Peeling Agents
Trichloroacetic acid (TCA) 10-35% is safe at lower concentrations. At higher concentrations ( greater than 50%) it has a tendency to scar.
Jessner""s peel is a combination of salicylic acid (14%), lactic acid (14%), and resorcinol (14%) in alcohol.
Salicylic acid has been used for several decades and is found in various medications ranging from 4% to 17% concentrations.
Carbon Dioxide uses a solid block of CO2 ice dipped in an acetone-alcohol mixture and applied to the skin for 5-15 seconds depending on the desired depth.
Alpha hydroxy acid peels include lactic acid, glycolic acid, tartaric acid and malic acid. Various concentrations can be purchased ranging from 10% to 70% concentrations.
Medium Depth Peels
Combinations peels such as CO2 and TCA 35%, Jessner""s and TCA 35%, and Glycolic and TCA 35% are currently being used.
TCA 50% is seldom used today because of risk of scarring.
Full strength phenol (88%) is very caustic an causes immediate keratin agglutination preventing further penetration.
Pyruvic acid is also rarely used today because of difficulty in controlling depth of penetration. An ethyl pyruvate is currently being developed to overcome this issue.
Deep Peels
The Baker Gordon peel is one of the most effective peeling agents currently available. The phenol produces a layer of collagen that is thicker than that produced by laser. However the Baker Gordon formula is not often used today because of laser resurfacing technology.
The compositions proposed under present invention are not acids nor do they employ freezing. They are protein synthesis inhibitors (PSIs). Accordingly a brief background about protein synthesis and cellular function is presented.
The most fundamental function a cell is protein synthesis (i.e. expression of its DNA). Proteins make up xcx9c60% of a dry cell""s mass by weight. In very broad and general terms, as cells mature and differentiate in the body, they reach an equilibrium in protein synthesis and protein degradation and settle down to perform their given function in this relative state of homeostasis. There are two notable exceptions that cause massive perturbations to this homeostasis: 1) when a cell is called upon to grow and divide and 2) when certain secretory cells are called upon to produce large amounts of proteins for secretion. Although the cell signaling signaling pathways, intracellular transduction pathways, and spectrum of protein(s) to be produced are quite different in growth versus secretion, normal growth and secretion events share one major similarity in their end result: massively accelerated protein synthesis. A cell that is called on to grow (cycling cell) has as much as 5 times the protein synthesis activity of a non cycling cell and needs between 2,000 and 5,000 different enzymes and structural proteins to grow and divide. Likewise, secretory cells such as those of the immune system become protein factories producing massive amounts of antibodies, mediators, growth factors, or other proteins when stimulated to do so.
There are also abnormal conditions such as cancer and viral infections that share the same property of hyperactive protein synthesis versus normal quiescent cells. Cancer is a growth and divide type event, and even though the signaling mechanism is different in that it is self-induced intracellularly by several genetic mutations, the end result is also hyperaccelerated protein synthesis characteristic of a cycling cell. Viruses invade a cell, parasitize the host cellular machinery, and convert the cell into a factory producing massive amounts of viral proteins, much like a secretory cell.
Inhibiting protein synthesis affects cells in a dose dependent manner and affects actively cycling cells differently than non cycling cells. At low doses, protein synthesis inhibitors (PSIs) stop actively cycling cells from cycling without killing them (hereinafter referred to as inhibitory or G zero inducing dose). Inhibitory doses also stop hyperaccelerated protein synthesis by secretory cells. At moderate doses PSIs exhibit toxicity to actively cycling cells (hereinafter referred to as the cytotoxic dose). At high doses, PSIs exhibit toxicity to all cells (hereinafter referred to as the toxic dose).
There are roughly 210 epithelial cell types in the body, and only a small handful are normally actively cycling. These include the epidermis, hair, bone marrow, and gastrointestinal mucosa. Epidermal cells cycle on a roughly 24 hour clock and as such would be susceptible to cytotoxicity from PSIs at dose levels not toxic to normal non rapidly proliferating cells. Non nucleated cells such as the non nucleated epidermal squames at the very top of the epidermis would not be affected. The collagen matrix below the epidermis would not be affected. This presents the opportunity for a highly selective epidermal chemexfoliation of the living epidermal cells sandwiched between the epidermal squames on top and the collagen on bottom.
Novelty and Unobviousnessxe2x80x94Overview
Present invention takes a fairly unobvious view and considers the epidermis a xe2x80x9csuper cancerxe2x80x9d. Epidermal basal cells cycle on a roughly 24 hour clock. By contrast, if tumor cells cycled on a 24 hour clock a human would be dead in under a month from the time the tumor was initially detected. Starting with a fairly tiny, clinically undetectable, initial tumor of xcx9c1 Million cells (i.e. 1 xcexcl mass) and growing it to lethal burden at around a Trillion cells (1 L mass), requires only about 20 cell cycles of all the tumor cells (i.e. 1 M, 2,4,8,32,64,128,256,512,1 Bil, 2,4,8,16,32,64, 128, 256,512, 1 Tril.).
Novelty and Unobviousness Over Prior Art Use of Trichothecene
Prior art has attempted to use trichothecene against hyperproliferative conditions such as cancer, however they have failed. Anguidine, a simple trichothecene, was tested against cancer and abandoned after Phase II testing showed a low tumor response and considerable hematologic toxicity. Prior arts attempt to remedy this failure are embodied in U.S. Pat. Nos. 4,906,452 and 4,744,981 which propose conjugates of trichothecene with monoclonal antibodies to enhance delivery to the tumor and glycosylation of trichothecene to increase blood solubility. Present invention takes a novel and unobvious approach that is exactly opposite to prior art in several respects. First, present invention reverses direction of administration (i.e. administered from tissue side to blood versus prior arts direction of blood to tissue). Second, present invention embraces the non specific internalization properties to deliver the greatest doses to tissues it is applied to and depending on those tissues to retain the trichothecene, preventing it from reaching general circulation (versus prior arts targeted delivery by monoclonal antibodies). Third, present invention embraces the use of macrocyclic trichothecene (versus simple trichothecenes in prior art) because the macrocyclic ring enhances rapid non specific internalization further enhancing localization and preventing entry into the blood. Fourth, present invention embraces blood insolubility to prevent entry into the blood (versus prior art glycosylation).
The one nice thing that can be said about chemotherapeutics such as trichothecene is that they kill cleanly because they induce apoptosis. Trichothecenes are cytotoxic to rapidly dividing cells because they interfere with the large burst of protein synthesis that are critical at various points in the cell cycle. In response to this type of intracellular damage or disruption the cell invokes a method of cell death known as apoptosis. Similarly, locally toxic doses proposed under present invention also kill non cycling epidermal cells, from the inside, by preventing synthesis of proteins necessary to maintain cell viability. Apoptosis is a specialized type of cell death the does not initiate the massive immune xe2x80x9cinjury responsexe2x80x9d that cutting, freezing (which ruptures the cell membrane through ice crystal formation), or acid destruction does.
Novelty and Unobviousness Over Prior Art Chemexfoliants
Since neither non nucleated epidermal squames at the very top of the epidermis nor the collagen matrix below the epidermis is destroyed by protein synthesis inhibition, compositions of present invention provide a unique opportunity for a highly selective epidermal chemexfoliation of the living epidermal cells sandwiched between the epidermal squames on top and the collagen on bottom. Compositions of present invention are a much xe2x80x9ccleaner killxe2x80x9d over prior art as they do not cause widespread rupturing of the cell membranes and spillage of intracellular contents. Thus, compositions of present invention would tend to cause much less pain and inflammation relative to prior art compositions which use acids or combinations of acids (see eMedicine Journal summary of prior art enclosed).
Lastly, present invention will also provide novel treatment methods for conditions not currently treated or treatable by prior art chemexfoliants including, but not limited to, epidermal conditions such as Kaposi""s sarcoma warts, moles, and basal and squamous cell carcinomas.
Present invention proposes epidermal chemexfoliation by topical administration of therapeutically effective doses of trichothecene.